The pathogenesis of the chronic fatigue syndrome (CFS) includes severe and debilitating fatigue, orthostatic intolerance, and the disruption of hematological, autonomic, and cardiovascular function. Our preliminary findings suggest that: 1) reduced red blood cell (RBC) mass is a critical hematological marker of CFS; and 2) RBC mass expansion improves orthostatic tolerance and fatigue beyond that ascribed to plasma volume expansion alone. However, the physiologic mechanisms underlying the RBC mass treatment effect and the relationship of such mechanisms to individual differences in treatment response have not been elucidated. This proposed 5-year study will screen 150 CDC-defined CFS men and women and classify them into low and normal RBC mass groups. The CFS subjects (90 of 105 enrolled) will be studied before and after a 3-month intervention in a randomized double-blind, placebo-controlled study of pharmacotherapy to expand RBC mass; specifically, two CFS groups with low RBC (RBC-treated and placebo-treated) will be compared to another CFS group with normal RBC mass (standard and usual care). To assess whether the diminished cardiac function, characteristic of CFS orthostatic intolerance, is a consequence of myocardial origin, echocardiographic evaluation of left ventricular structure and function (left ventricular mass and wall thickness, compliance, and contractility) will be performed. In addition, autonomic integrity will be assessed during a standardized battery of tests (supine rest, paced respiration, Valsalva maneuver, lying-to standing, and sustained handgrip); baroreceptor sensitivity and alpha- and beta-adrenoceptor sensitivity will he tested using adrenoceptor pharmacologic challenge (phenylephrine, isoproterenol). To determine orthostatic susceptibility, a 70 head-up tilt (HUT) test combined with beta-adrenoceptor infusion at 2 mug/min (and then again at 5 mug/min, if the previous HUT failed to induce orthostatic hypotension) will be performed. We will further examine the treatment effect on exertional fatigue and hemodynamic and autonomic physiologic response to the HUT tests. Finally, the relation between the criterion (orthostatic hypotension susceptibility) and the predictors (hemodynamic, autonomic, cardiac structure/function and baroreceptor, alpha-adrenoceptor and beta-adrenoceptor sensitivities) will be evaluated to determine the extent to which the predictors are mediating the treatment effects on orthostatic hypotension susceptibility.